Uterine mullerian adenosarcoma is a very rare tumor clinically. Shi et al1 has reported 9 uterine adenosarcomas among 116 uterine sarcomas during 11 years in West China Second Hospital. It consists of benign or atypical neoplastic glands within a sarcomatous stroma and represents only 8% of uterine sarcomas. Its histological features are intermediate between the benign adenofibroma and the highly malignant carcinosarcoma and biologic behaviors show low malignant potential.2 In this report, we analyzed nine cases of uterine mullerian adenosarcoma, and the clinical characteristics, diagnosis, treatment and prognosis of this tumor were discussed.
Between January 2003 and February 2009, nine patients diagnosed as uterine mullerian adenosarcoma in surgical pathology files were treated in Peking Union Medical College Hospital. Of the nine cases, six were located in the endometrium and the remaining three were originated from cervix. This original research was approved by the local institutional review board.
The patients ranged in age from 18 to 47 years (average 33.8 years, median 31 years). Six women were ≤40 years of age. Two patients were postmenopausal. The mean gravity and parity were 1.2 and 0.6 (range 0-4 and 0-2) respectively. Six women were nulligravida.
The chief complaints of 6 uterine endometrial mullerian adenosarcomas were abnormal vaginal bleeding (5 cases); pelvic pain (3 cases) and abnormal vaginal discharge (one case). These tumors tended to appear as exophytic polypoid masses growing inside the uterine cavity and occasionally extended from the uterus via cervical orifice. Physical examinations showed enlarged uterus (3 cases), cervical neoplasm protruding from the external cervical os or palpable pelvic mass (2 cases, each) and vaginal mass (one case).
The presenting manifestations of cervical adenosarcoma included irregular menstruation, repeating vaginal discharge and evacuation of tissues from vagina. Cervical polypoid neoplasms were the presenting sign in all the three patients with an enlarged uterus in one patient.
The patients were staged according to FIGO staging criteria for endometrial cancer and cervical cancer. Of the six uterine endometrial adenosarcoma, there were one stage Ia, two stage Ib, one stage Ic and two stage III. Three cervical adenosarcoma patients were all stage I (Table).
Primary diagnosis and pathological findings
Six patients were diagnosed correctly before surgery through histologic examinations of resected lesions or reviewing of pathological slides from other hospitals; two patients were interpreted as endometrial stromal tumors; and the other one was considered to be endometrioma- like polypus.
The pathologic features were summarized in Table. On gross examination, maximum tumor size ranged from 1.0 to 12.0 cm (mean, 6.1 cm). Tumors exhibited polypoid, papillary or bulbous growth pattern and they had the appearance of grayish pink, grayish white or dark tan in color. The cutting surface was commonly solid and jelly-like cyst fluid was noted in two cases.
Microscopically, the tumors were composed of benign or atypical-appearing neoplastic glands within a sarcomatous stroma which appeared as periglandular cuffs or intraglandular polypoid projections of increased cellular structure (Figure 1). The mitotic rate was 5-15 per 10 high-power fields. No muscular invasion was found in four patients and superficial muscular invasion in two patients; deep muscular invasion existed in two patients. Sarcomatous overgrowth in which a pure sarcomatous component occupied at least 25% of the tumor was present in three cases (Figure 2, Table). Heterologous elements which were striated muscle and chondrometaplasia were identified in two patients. Immunohistochemically, the stromal cells were negative with CD10 in four out of six cases. The other two cases were focally positive with CD10.
Treatment and prognosis
Three patients were managed by complete local excision of the tumors in cervix or uterine cavity for fertility sparing but unfortunately one of them recurred more than two years later and underwent hysterectomy eventually. Other patients' treatment consisted of hysterectomy in three patients, radical hysterectomy in one patient and cytoreductive surgery in two patients. Conservation of unilateral or bilateral ovaries was performed in five cases. After surgery, seven patients received chemotherapy; one was treated with radiotherapy; and three patients were given hormone therapy (methyl acetoxyprogesterone). Follow-up data were available for all the patients with a mean interval of 2.64 years (range, 0.50 to 6.50 years). Seven patients were alive and well with no evidence of recurrence. One patient of clinical stage III containing sarcomatous overgrowth died from recurrence 1.25 years after surgery (case 3). The other one developed a recurrent tumor 2.33 years after local excision of the tumor in uterine cavity and she remained healthy since hysterectomy (case 4, Table).
Mullerian adenosarcoma is a rare tumor first described by Clement and Scully in 1974.2 It exhibits a benign glandular element and a malignant stroma. This tumor most commonly occurs in the endometrium and less frequently in the extrauterine genital tract. Uterine endometrial adenosarcomas were typically found in postmenopausal women with the median age in extensive series 58 years.3 Compared with them, cervical adenosarcomas tended to appear more often in younger women with the average age at presentation 31 years.4 Our study covered younger women with the median age of 31 years. Six women were ≤40 years of age. Two nulligravida with cervical adenosarcoma were only 18 and 23 years. In comparison to other uterine malignant tumors, uterine mullerian adenosarcomas presented with nonspecific symptoms and signs. The most common clinical presentations were abnormal vaginal bleeding and pelvic pain. In some patients, the tumors might protrude through the external cervical os and vaginal/cervical masses could be seen on physical examinations. Some patients had an enlarged uterus or palpable pelvic mass. Patients with cervical adenosarcoma often presented with polypoid neoplasms and might be confused with benign appearing cervical polyps.
Diagnosis of uterine mullerian adenosarcoma depends on pathological examination of removed tumors from uterine cavity or cervix. Some researchers3 have recommended that diagnosis of adenosarcoma be made when one or more of the following are present: 1) stromal mitotic count of two or more per ten high-power fields; 2) marked stromal cellularity; and 3) more than a mild degree of stromal nuclear atypia. The stromal component may consist of homologous elements and less frequently, heterologous elements can be found such as cartilage and striated muscle.5 The differential diagnosis includes benign lesions such as adenofibroma, adenomyoma, polyp in uterine cavity or cervix and malignant lesions such as low grade endometrial stromal sarcoma, malignant mixed mullerian tumors and embryonal rhabdomyosarcoma, etc. Carefully observing component, structure, heteromorphism and nuclear mitosis of the tumor may be helpful to reach a definite pathological diagnosis. As the lesions are not well-distributed and often overlap with benign areas, it is important to do biopsy from diseased regions thoroughly. In this study six out of nine patients were diagnosed clearly and correctly before operations. Two patients were considered to be “endometrial stromal sarcoma” and the remaining one patient was suspected of “endometrioma-like polypus”.
This study demonstrated that most uterine mullerian adenosarcomas were generally of low-grade malignancy. Seven out of nine cases were stage I patients. Definitive staging surgery for uterine endometrial adenosarcoma comprises total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node sampling, omentectomy and peritoneal washing. As for cervical adenosarcoma, the relative rarity has made the assessment of the most effective management difficult. Most authors recommend total abdominal hysterectomy, usually accompanied by bilateral salpingo-oophorectomy. Opinions upon the practical value of staging by lymphadenectomy during primary surgery diverge between gynecologists. Those with poor prognostic factors such as deep myometrial invasion or sarcomatous overgrowth may benefit from adjuvant chemotherapy and radiotherapy.5-8 Six patients in this study were treated with hysterectomy while the other three underwent local excision of the tumors in cervix or uterine cavity. After surgery, seven patients were placed on chemotherapy, radiotherapy or hormone therapy.
In this study, more conservative surgical management has been employed in young patients who are willing to preserve fertilities. Two patients with cervical adenosarcoma underwent local complete excision of the tumors and pathology demonstrated no residual in the cutting edge. Follow-up showed no evidence of recurrence for 1.67 and 6.50 years separately. Local excision may be an alternative in young patients with pedunculated cervical adenosarcomas and involved stalks, thus, allowing conservation of reproductive function.3,9,10 Geisler et al7 reported that a young woman with stage IB1 cervical adenosarcoma was successfully treated by a robotically assisted total laparoscopic radical trachelectomy with cerclage as well as pelvic and para-aortic lymphadenectomy for fertility sparing. In contrast to cervical adenosarcoma, however, in uterine endometrial adenosarcoma, recurrence rates as high as 50%-85% have been reported after conservative surgery.3,11 This may be related to the incomplete removal of tumors. In this study, a young patient with uterine endometrial adenosarcoma underwent local excision and then was placed on three courses of PEI chemotherapy and hormone therapy. More than two years later the tumor recurred and hysterectomy was carried out. Pathology indicated that the disease had infiltrated superficial myometrium. Now the patient is disease-free.
In this research, conservation of unilateral or bilateral ovaries was performed in five women and no one recurred in the regular follow-up. Of the four patients who underwent bilateral salpingo-oothectomy, only one patient of stage III suffered from ovarian metastasis. Ozmen et al12 reported conservation of both ovaries along with definitive staging surgery and adjuvant chemotherapy was performed in a 14-year-old girl with uterine adenosarcoma. After 30 months, she had no evidence of disease. Michener et al13 indicated that the risk of ovarian involvement at initial surgery was rare (2%). The author also suggested the reliability of ovarian conservation in young patients with disease confined to the uterus. Then biopsy of bilateral ovaries was necessary to exclude tumor infiltration.
Uterine mullerian adenosarcoma is generally regarded as being low malignant potential. Distant metastases are rare, whereas local recurrences are more common. Clement and Scully3 reported 100 patients with uterine mullerian adenosarcoma. Recurrent tumor developed in 23 cases and approximately one third of whom recurred five or more years after hysterectomy. Recurrent tumor was almost always confined to the vagina, pelvis, or abdomen. Distant blood-borne metastases occurred in only two cases.14 Risk factors associated with recurrence and metastasis in literatures included deep myometrial invasion, lymph-vascular space invasion, sarcomatous overgrowth, spread outside the uterus and the presence of heterologous elements in primary tumor, etc.14,15 This study revealed that the presence of late clinical stage and sarcomatous overgrowth were unfavorable factors affecting recurrence and prognosis. Recurrent tumor developed in two of the nine cases and one patient died from tumor progression. One patient on stage III with sarcomatous overgrowth experienced a very aggressive clinical course and recurred nine months after surgery. She presented with a rapidly growing mass in vagina and died from recurrence eventually. The other patient of early stage disease underwent removal of the mass in uterine cavity which did not show sarcomatous overgrowth. The tumor recurred 2.33 years later and presented with occupation in uterine cavity and cervical canal. Then hysterectomy was performed and pathology showing superficial myometrium was involved. To our knowledge the recurrence might be associated with incomplete removal of the mass in uterine cavity during the primary operation. After hysterectomy she remained in good health.
In conclusion, uterine mullerian adenosarcoma is a rare tumor without specific clinical symptoms and signs. The diagnosis depends on pathomorphologic observation. The tumors show low malignant potential and the vast majority are at early stage. Surgical excision is the main treatment strategy with a good prognosis in early stage disease by complete removal of tumors. The prognosis is poor in advanced adenosarcoma with sarcomatous overgrowth. Fertility-sparing surgery is feasible in those young patients with superficial cervical adenosarcoma or tumors confined to a local area of cervix. Due to the relatively high rate of recurrence, long-term follow-up is recommended.
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